Validation of a 22-gene Genomic Classifier in the NRG Oncology/RTOG 9202, 9413 and 9902 Phase III Randomized Trials: A Biopsy-Based Individual Patient Meta-Analysis in High-Risk Prostate Cancer

Decipher is a prognostic 22-gene genomic classifier (GC) prospectively validated post-prostatectomy. Herein, we validate the performance of the GC in pre-treatment biopsy samples within the context of three randomized phase III high-risk definitive radiotherapy trials. Following a pre-specified and approved CTEP-CCSC analysis plan (NRG-GU-TS006), we obtained all available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on NRG/RTOG 9202, 9413, and 9902 phase III randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability of GC for distant metastases (DM), and secondary was prostate cancer-specific mortality (PCSM) and overall survival (OS), with Cox multivariable analyses (MVA). GC scores were obtained on 385 samples (n = 90 on 9202, n = 172 on 9413, and n = 123 on 9902), of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9, 13). On MVA, the GC (per 0.1 unit) was independently associated with DM (HR 1.24, 95% CI 1.11-1.39), PCSM (HR 1.27, 95% CI 1.13-1.43), and OS (HR 1.12, 95% CI 1.05-1.20) after adjusting for age, PSA, Gleason score, cT-stage, trial, and randomized treatment arm. For categorical GC, on MVA, GC score ≥ 0.45 (representing the intermediate and high GC categories) had worse DM (HR 2.18, 95% CI 1.25-3.80), PCSM (HR 2.34, 95% CI 1.31-4.16), and OS (HR 1.45, 95% CI 1.03-2.04) outcomes as compared to those with low GC. Cumulative incidence of distant-metastasis at 10-years was 29% (95% CI 20-38%) for intermediate/high GC vs 13% (95% CI 7-18%) for low GC. For the subset with GC > 0.85, the threshold for inclusion in the intensification study of NRG GU009 (PREDICT-RT), at 5-years and 10-years DM was 29% (95% CI 7-52%) and 41% (95% CI 17-66%). GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy (ADT). This is the first validation of any gene expression biomarker on pre-treatment biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT will further determine the optimal therapy based on GC score. NCT0451371

The Long-Term Care Insurance Program in Israel: solidarity with the elderly in a changing society

<p>Abstract</p> <p>The Long-Term Care Insurance Program (LTCIP) in Israel is a social security program administered by the National Insurance Institute (NII) since 1988. LTCIP focuses on home-based personal care services. Differently from most other programs under the responsibility of the NII, LTCIP benefits are in-kind benefits and are delivered via multiple for-profit and not-for-profit organizations. In recent years LTCIP has been the target of various legal amendments and numerous administrative changes. While many of these changes may have had significant effects on individuals, they have not altered the fundamental principles of the program. Thus, many of the characteristics of beneficiaries have remained quite stable over the years; other characteristics of the population of beneficiaries have changed over the years reflecting the aging of Israeli society. A central issue related to LTCIP is whether benefits are adequate to meet the needs of the growing elderly population of Israel. While the generosity of LTCIP benefits is questionable, economic and political struggles have limited the scope of changes introduced thus far.</p

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1–3c (modified to stage 2–3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1–5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57–0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3–91·8) in the neratinib group and 87·7% (85·7–89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3–4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses—ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast—without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events